The present sequential trial design takes advantage of a window of opportunity to assess PS-341 alone in aggressive large cell lymphomas. However, because recurrent DLBCL is potentially curable with EPOCH chemotherapy alone (20%) or stem cell transplant (25%), patients who do not enter CR with PS-341 will receive PS-341 and EPOCH chemotherapy. EPOCH chemotherapy was selected because its efficacy has been validated in both recurrent and untreated DLBCL and is a potentially curable regimen. Hence, if PS-341 is shown to be active, it could potentially be combined with EPOCH for the initial treatment of poor prognosis NF-kB-expressing DLBCL. The primary study objectives are: 1) Assess response of PS-341 in diffuse large B-cell lymphoma (DLBCL) and within the ABC and GCB molecular subtypes; 2) Assess toxicity and safe tolerated dose of PS-341 and EPOCH in DLBCL; 3) Obtain pilot information on response of PS-341 and EPOCH in DLBCL. The secondary objectives are: 4) Assess biological effect of PS-341 on DLBCL tumor biopsies using microarray and IHC, including bcl-2 and NF-kB; 5) Assess markers of drug resistance (bcl-2, MIB-1, p53) on response to PS-341 and EPOCH. Novel treatment approaches are needed for lymphoma patients, including those with aggressive AIDS-related lymphomas. This study showed that bortezomib alone had a low response rate but improved the activity of DA-EPOCH-R in ABC compared with GCB DLBCL.